Background: Asthma is the most common reason for hospitalization of children in both military and civilian hospitals. In children with asthma, pulmonary exposure to allergen results in damage to bronchioles by invasion of eosinophils. Eosinophils are inflammatory cells, have limited life spans, and must be continually renewed from hematopoietic tissue. We adapted an animal model of asthma to our laboratory for studies of the effect of pulmonary allergen exposure on eosinophil progenitor cells (CFU-eo). These studies have revealed that CFU-eo numbers are elevated in the bone marrow of asthmatic mice following pulmonary allergen exposure. IL-5 is the primary cytokine that regulates eosinophil production and was originally thought to be synthesized exclusively by T lymphocytes. We demonstrated that fibroblastic bone marrow stromal cells produce IL-5 and that stromal cells regulate eosinophil production in vitro. The relative role of bone marrow stromal cells and T lymphocytes in eosinophilia that accompanies chronic asthma has not been investigated.

Objective/Hypothesis: Our working hypothesis based on data discussed in this application is that eosinophil production is regulated by both bone marrow stromal cells and T lymphocytes and that both cell types contribute to eosinophilia associated with asthma. The primary objective of this study is to determine the relative role of stromal cells and T lymphocytes in normal and asthmatic eosinophil production.

Specific Aim: Experiments detailed in this proposal aim to determine the relative contribution of bone marrow stromal cells and T lymphocytes in eosinophilia of asthma. The effect of inflammatory mediators on stromal cell support of eosinophilopoiesis and the durability of these responses will also be investigated.

Study Design: These experiments will utilize a well-established mouse model of asthma. In vivo experiments will compare the effect allergen exposure in wild-type and athymic nude Balb/c mice. In vitro bone marrow cultures will be employed to investigate specific cellular and molecular mechanisms that regulate the tempo of eosinophil production.

Relevance: The incidence of asthma is rapidly increasing in civilian and military children. Better understanding of the cellular and molecular mechanisms involved in the initiation and progression of the disease is essential for design of more effective intervention strategies to interrupt the growing incidence of this disease.